Antibodies have been known since before the 20th century to play an important role in immunological protection against infectious organisms. The immune system cells that produce antibodies are B-lymphocytes. There are four major classes: immunoglobulin M (IgM), IgG, IgA, and IgE, but IgG is by far the most prevalent class, comprising about 90% of all antibodies in adults. Each class of antibody has a specific role in immunity, including primary and secondary immune responses, antigen inactivation and allergic reactions. IgG is the only class of antibody that can pass the placental barrier. Therefore, IgG provides the only antibody protection for newborns until their own immune system is able to contribute to antibody production.
Antibody molecules have two ends. One end is the antigen-specific receptor, which is highly variable and engenders each antibody with the capacity to bind a specific molecular shape. The other end, referred to as Fc, has sequence and structural similarities within a class and confers the ability to bind to receptors on immune cells. In a perfectly operating immune system, the diverse specificities of the antigen specific receptor engenders the host with a diverse repertoire of antibodies with the ability to bind to a wide array of foreign infectious microorganisms, the result being destruction of the microbe and immunity.
Autoimmune diseases occur when the immune system erroneously senses that normal tissue is foreign and attacks it. One of the most prevalent immunological participants in autoimmune destruction is autoantibodies, which are normal antibody molecules that have gone awry and destroy normal tissue. This leads to many types of autoimmune diseases, including systemic lupus erythematosus (SLE). Systemic lupus erythematosus (SLE) is a prototypic disease of systemic antibody dysregulation with the common feature of hypergammaglobulinemia, anti-DNA features and anti-nuclear protein antibodies, and immune complexes that accumulate at many sites including the kidney glomeruli, vascular system, joints and skin (Theofilopolos and Dixon, Adv. Immunol. 37: 296–390 (1985); Theofilopolos and Dixon, Immunol. Rev. 55:179–215 (1981); Boumpas et al, Ann Int. Med. 122:940 (1995)). The severity can range from mild to very severe, from minimally debilitating to lethal.
Treatment of autoimmune diseases usually includes therapy with nonsteroidal anti-inflammatory drugs (NSAID) or corticosteroids, which generally suppress the immune system by, for example, inhibiting mediators of the inflammatory process. Although effective, there are many potentially harmful side effects associated with these treatments, including stomach erosions, bleeding ulcers, high blood pressure and hepatic, and renal dysfunction. In cases where renal function is severely impaired, kidney transplants only provide temporary relief because of the systemic nature of the autoimmune disease. The identification of less radical and more specific methods of prevention and treatment of SLE is thus a matter of considerable importance.
One of the most promising new treatments for autoimmune diseases is the periodic administration of patients with high doses of antibodies. This treatment is very expensive and yields only transient relief, but relative to other treatment regimens available is highly effective with lower incidences of harmful side effects. The administration of high doses of antibodies into a patient with a disease caused by antibodies seems contradictory. However, the identification of the mechanism by which high dose antibody treatments work, and targeting that mechanism directly, could lead to far more effective therapies to treat autoimmune disease.
One such hypothesis involves the endothelial receptor FcRn (FcRp/Fcgrt1). FcRn is a novel member of a family of proteins that perform varied immunological functions. It is known that the FcRn molecule is expressed in the vascular endothelium along with other tissues of adult animals, including mice and humans. FcRn binds to antibody molecules, but only those from the IgG class. Bjorkman and Simister (PNAS 89:638–42, 1992) solved the crystal structure of the FcRn/IgG complex, proving that a receptor/ligand relationship exists between the two molecules.
Most molecules, including antibodies, only remain a short amount of time in the circulation because they are captured by vascular endothelial cells and then efficiently destroyed by a process referred to as catabolism. The existence of a receptor for IgG molecules which greatly slows catabolism of the IgG molecules has been previously proposed. The proposed receptor is postulated to do this by binding most IgG molecules before they are destroyed, and then recycling the antibodies back into the bloodstream thereby increasing the half-life of IgG. Several investigators have indirectly demonstrated such a protective effect by coupling the Fc region of IgG to different polypeptides to improve stability of the polypeptide (U.S. Pat. No. 6,096,871, U.S. Pat. No. 6,121,022). In addition, PCT Application WO 97/34631 describes the use of immunoglobulin-like domains in increasing the stability and longevity of pharmaceutical compositions for therapeutic and diagnostic purposes.